Eosinophilic bronchitis in asthma: A model for establishing dose-response and relative potency of inhaled corticosteroids

doi:10.1016/j.jaci.2006.01.045

Journal of Allergy and Clinical Immunology

Volume 117, Issue 5, May 2006, Pages 989-994

https://doi.org/10.1016/j.jaci.2006.01.045 Get rights and content

Background

Newer generations and formulations of inhaled corticosteroids have necessitated the development of a clinically relevant model to compare their clinical potency.

Objective

We evaluated whether sputum eosinophil counts could demonstrate a dose-response to inhaled corticosteroids, and compared the response with other inflammatory markers.

Methods

Fourteen steroid-naive patients with asthma with an initial sputum eosinophilia of ≥2.5% entered a 6-week sequential, placebo-controlled, patient-blinded, cumulative dose-response study. After 7 days of placebo, they received incremental doses of fluticasone propionate (FP), 50, 100, 200, and 400 μg/d, each for 7 days. Measurements were made of sputum and blood eosinophils, exhaled nitric oxide, spirometry, airway responsiveness to methacholine (methacholine PC₂₀), and symptom scores before and after each dose.

Results

Sputum eosinophils and exhaled nitric oxide were extremely sensitive to the effects of FP, and exhibited significant dose-dependent reductions of 99.4% and 99.8 parts per billion, respectively, where each variable was expressed per 100 μg/d FP. This compared with a 0.5 doubling dose increase of airway responsiveness to methacholine and a 0.3 decrease in symptom scores. Airway responsiveness to methacholine was the only variable that increased throughout the study.

Conclusion

These results suggest that the model of eosinophilic bronchitis could be used to compare the effect of cumulative doses of an inhaled corticosteroid delivered by different types of delivery systems or preparations using a relatively small number of patients.

Clinical implications

Future clinical studies based on this model will allow clinicians to make informed decisions regarding the relative potencies of different inhaled corticosteroids.

Section snippets

Patients

Fourteen nonsmoking adults with asthma were recruited by advertising in local media and pharmacies, as well as from outpatient clinics of the hospital. Asthma was diagnosed according to established guidelines.²² Additional clinical details are provided in the online repository at www.jacionline.org. For the purpose of the study, sputum eosinophilia was defined as ≥2.5% of the inflammatory cells present on induced sputum analysis, and only those patients conforming to this at both the screening

Effects on markers of airway inflammation

When related to baseline, the percentage of sputum eosinophils were significantly lower after treatment with 100, 200, and 400 μg FP/d for 1 week, absolute eosinophil counts only after 200 and 400 μg FP, eNO concentration after treatment with FP at all time points, and symptom scores after 100 and 400 μg FP (P < .05). Methacholine PC₂₀ increased after treatment with 50 μg, 100 μg, 200 μg, and 400 μg FP by 0.19, 0.31, 0.82, and 1.26 doubling doses, respectively, and was significantly different

Discussion

In this study, we have observed that 4 incremental doses of FP resulted in a significant reduction of sputum eosinophils and eNO and a significant improvement in methacholine PC₂₀ and symptom scores. In addition, the steep dose-response curves demonstrated in this study were achieved with a relatively small number of patients (n = 14).

Sputum eosinophils and eNO were extremely sensitive to low doses of inhaled FP, with 86.5% and 65%, respectively, of the total change from baseline occurring

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In contrast, it is easier to demonstrate a dose–response to biomarkers, and the most commonly studied are FeNO,22 sputum eosinophils,6 and measures of airway responsiveness in response to direct (eg, methacholine) or indirect (eg, adenosine monophosphate, mannitol, exercise, or allergen) airway provocation challenges. While FeNO, sputum eosinophils, and indirect challenge responses can be demonstrated relatively quickly, the changes in methacholine responses are demonstrated over a prolonged period of time.6 Mometasone, in particular, has been demonstrated to show a dose-dependent attenuation of allergen-induced late asthma response and sputum eosinophils.23
A well-controlled study in patients with allergic asthma was warranted to assess dose-dependency between fractional concentration of exhaled nitric oxide (FeNO) and sputum eosinophils to a combination of an inhaled corticosteroid plus a long-acting β₂-agonist. We sought to characterize the dose-dependency of mometasone furoate/formoterol (MF/F) using FeNO and sputum eosinophil percentage as surrogates of airway inflammation in subjects with allergic asthma.
Following a 2-week, open-label run-in, 93 subjects (≥12 y) using only short-acting beta agonist reliever medication as needed, were randomized to twice daily (BID) placebo; MF/F 100/10 μg, 200/10 μg, or 400/10 μg (via pressurized metered-dose inhaler [MDI]); MF-MDI 200 μg; or MF 200 μg via dry powder inhaler (DPI) during a 2-week, double-blind treatment period.
All active treatments demonstrated significant percentage reductions from baseline in FeNO compared with placebo at all time points (P ≤ 0.034). At endpoint, mean MF/F treatment group FeNO reductions ranged from −35.3% to −61.4%. Sputum eosinophil percentage reductions from baseline were significant compared with placebo for the MF/F 200/10 μg, MF/F 400/10 μg, and MF-DPI 200 μg groups at endpoint (P ≤ 0.023). Escalating MF/F doses significantly reduced both FeNO (P ≤ 0.001) and sputum eosinophil (P ≤ 0.022) levels in a dose-dependent manner at all time points. All treatments were well tolerated; no serious adverse events were observed.
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Glucocorticoids are widely used to treat various inflammatory lung diseases. Acting via the glucocorticoid receptor (GR), they exert clinical effects predominantly by modulating gene transcription. This may be to either induce (transactivate) or repress (transrepress) gene transcription. However, certain individuals, including those who smoke, have certain asthma phenotypes, chronic obstructive pulmonary disease (COPD) or some interstitial diseases may respond poorly to the beneficial effects of glucocorticoids. In these cases, high dose, often oral or parental, glucocorticoids are typically prescribed. This generally leads to adverse effects that compromise clinical utility. There is, therefore, a need to enhance the clinical efficacy of glucocorticoids while minimizing adverse effects. In this context, a long-acting β₂-adrenoceptor agonist (LABA) can enhance the clinical efficacy of an inhaled corticosteroid (ICS) in asthma and COPD. Furthermore, LABAs can augment glucocorticoid-dependent gene expression and this action may account for some of the benefits of LABA/ICS combination therapies when compared to ICS given as a monotherapy. In addition to metabolic genes and other adverse effects that are induced by glucocorticoids, there are many other glucocorticoid-inducible genes that have significant anti-inflammatory potential. We therefore advocate a move away from the search for ligands of GR that dissociate transactivation from transrepression. Instead, we submit that ligands should be functionally screened by virtue of their ability to induce or repress biologically-relevant genes in target tissues. In this review, we discuss pharmacological methods by which selective GR modulators and “add-on” therapies may be exploited to improve the clinical efficacy of glucocorticoids while reducing potential adverse effects.

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Supported by the Therapeutics Products Programme of Health Canada, Ottawa, Canada. GlaxoSmithKline, Canada, supplied all study medications but provided no other financial support.

Disclosure of potential conflict of interest: R. Leigh received honoraria from Altana, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Pfizer, and Sanofi-Aventis Pharmaceuticals. K. Parameswaran has received research grants from GlaxoSmithKline, AstraZeneca, and Sepracor, and has received honoraria from Merck Frost, AstraZeneca, and GlaxoSmithKline. F. Hargreave is on the GlaxoSmithKline advisory board. The rest of the authors have declared that they have no conflict of interest.

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Asthma diagnosis and treatmentEosinophilic bronchitis in asthma: A model for establishing dose-response and relative potency of inhaled corticosteroids

Background

Objective

Methods

Results

Conclusion

Clinical implications

Section snippets

Patients

Effects on markers of airway inflammation

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Lancet

Chest

J Allergy Clin Immunol

Am J Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Med

Asthma

N Engl J Med

Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma

Am Rev Respir Dis

Low-dose inhaled corticosteroids and the prevention of death from asthma

N Engl J Med

Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial

Am J Respir Crit Care Med

Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group

N Engl J Med

An inhaled steroid improves markers of airway inflammation in patients with mild asthma

Eur Respir J

Asthma diagnosis and treatment
Eosinophilic bronchitis in asthma: A model for establishing dose-response and relative potency of inhaled corticosteroids